This is a multidisciplinary project designed to delineate the genetic architecture of spina bifida, a developmental malformation resulting from abnormal or incomplete closure of the caudal end of the neural tube. The study involves the enrollment of a large sample of families ascertained on the basis of one or more members with spina bifida, and the collection of detailed information on potentially important phenotypic covariates. In addition, a highly selected panel of candidate genes will be evaluated using association based approaches. Ultimately, information obtained from the proposed studies will allow us to further define the biochemical and developmental pathways involved in the development of the neural tube, and to evaluate approaches for population based screening and prevention of spina bifida.